Segmental duplication and subsequent mutation of genetic material is one of the primary forces by which genomes evolve. While genomic duplication is fundamental to the emergence of genes with new functions, it is also a significant source of genomic instability associated with recurrent chromosomal structural rearrangement and disease. Our recent analysis of the human genome has revealed an extraordinary degree of recent evolutionary plasticity--at the level of both the genome and the gene. We hypothesize that the process of segmental duplication and the emergence of new gene function have been coordinated through processes of gene conversion and non-allelic homologous recombination. To test this model, this renewal application will focus on the comparative primate analysis of about 4 Mb of euchromatic sequence from human chromosome 16 which has been the target of a series of complex intrachromosomal duplication events as well as the site for the emergence of a novel human gene family. Combining large-scale comparative sequencing, phylogenetics, FISH, microarray comparative genomic hybridization and computational analysis, the proposal will address three fundamental questions: 1) How did such a complex architecture of chromosome-specific duplications evolve so rapidly? 2) How did this expansion correlate with the emergence of a novel gene family? 3) Does this architecture contribute to large-scale structural variation within and between contemporary primate populations? Due to the recent nature of these duplications and a reference human genome for comparison, the results of these studies provide a unique opportunity to investigate the molecular events and mechanisms(s) underlying this form of human genome evolution. Furthermore, these detailed studies should provide framework for a more global understanding of the impact of segmental duplications on large-scale genomic variation and disease.